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Andersen Tawil Syndrome (ATS) is a neurological channelopathy caused by mutations in the KCNJ2 gene that encodes the ubiquitously expressed Kir2.1 potassium channel. The syndrome is characterised by episodic weakness, cardiac arrythmias and dysmorphic features. However, the full extent of the multi-system phenotype is not well described. In-depth, multi-system phenotyping is required to inform diagnosis, and guide management. We report our findings following deep multimodal phenotyping across all systems in a large case series of 69 total patients, with comprehensive data for 52. As a national referral centre, we assessed point prevalence and showed it is higher than previously reported, at 0.105 per 100 000 population in England. While the classical phenotype of episodic weakness is recognised, we found that a quarter of our cohort have fixed myopathy and 13.5% required a wheelchair or gait aid. We identified frequent fatty infiltration on MRI and tubular aggregates on muscle biopsy emphasising the active myopathic process underpinning the potential for severe neuromuscular disability. Long exercise testing (LET) was not reliable in predicting neuromuscular symptoms. A normal LET was seen in five patients of whom four had episodic weakness. 67% of patients treated with acetazolamide reported a good neuromuscular response. 13% of the cohort required cardiac defibrillator or pacemaker insertion. An additional 23% reported syncope. Baseline electrocardiograms were not helpful in stratifying cardiac risk, but holter monitoring was. A subset of patients had no cardiac symptoms, but had abnormal holter monitor recordings which prompted medication treatment. We describe the utility of loop recorders to guide management in two such asymptomatic patients. Micrognathia was the most commonly reported skeletal feature, however 8% of patients did not have dysmorphic features and one third of patients had only mild dysmorphic features. We describe novel phenotypic features including abnormal echocardiogram in nine patients, prominent pain, fatigue and fasciculations. Five patients exhibited executive dysfunction and slowed processing which may be linked to central expression of KCNJ2. We report eight new KCNJ2 variants with in vitro functional data. Our series illustrates that ATS is not benign. We report marked neuromuscular morbidity and cardiac risk with multi-system involvement. Our key recommendations include proactive genetic screening of all family members of a proband. This is required, given the risk of cardiac arrhythmias among asymptomatic individuals, and a significant subset of ATS patients have no (or few) dysmorphic features or negative LET. We discuss recommendations for increased cardiac surveillance and neuropsychometry testing.

INTRODUCTION/AIMS: The aim of this study was to evaluate the sensitivity of the long exercise test (LET) in the diagnosis of periodic paralysis (PP) and assess correlations with clinical phenotypes and genotypes. METHODS: From an unselected cohort of 335 patients who had an LET we analysed 67 patients with genetic confirmation of PP and/or a positive LET. RESULTS: 32/45 patients with genetically confirmed PP had a significant decrement after exercise (sensitivity of 71%). Performing the short exercise test before the LET in the same hand confounded results in 4 patients. Sensitivity was highest in patients with frequent (daily or weekly) attacks (8/8, 100%), intermediate with up to monthly attacks (15/21, 71%) and lowest in those with rare attacks (9/16, 56%) (p=0.035, Mann-Whitney U test). Patients with a positive LET without confirmed PP mutation comprised those with typical PP phenotype and a group with atypical features. DISCUSSION: In our cohort, the LET is strongly correlated with the frequency of paralytic attacks suggesting a role as a functional marker. A negative test in the context of frequent attacks makes a diagnosis of PP unlikely but it does not rule out the condition in less severely affected patients. This article is protected by copyright. All rights reserved.

High throughput DNA sequencing is increasingly employed to diagnose single gene neurological and neuromuscular disorders. Large volumes of data present new challenges in data interpretation and its useful translation into clinical and genetic counselling for families. Even when a plausible gene is identified with confidence, interpretation of the clinical significance and inheritance pattern of variants can be challenging. We report our approach to evaluating variants in the skeletal muscle chloride channel ClC-1 identified in 223 probands with myotonia congenita (MC) as an example of these challenges. Sequencing of CLCN1, the gene that encodes CLC-1, is central to the diagnosis of MC. However, interpreting the pathogenicity and inheritance pattern of novel variants is notoriously difficult as both dominant and recessive mutations are reported throughout the channel sequence, ClC-1 structure-function is poorly understood and significant intra- and interfamilial variability in phenotype is reported. Heterologous expression systems to study functional consequences of CIC-1 variants are widely reported to aid the assessment of pathogenicity and inheritance pattern. However, heterogeneity of reported analyses does not allow for the systematic correlation of available functional and genetic data. We report the systematic evaluation of 95 CIC-1 variants in 223 probands, the largest reported patient cohort, in which we apply standardised functional analyses and correlate this with clinical assessment and inheritance pattern. Such correlation is important to determine if functional data improves the accuracy of variant interpretation and likely mode of inheritance. Our data provide an evidence-based approach that functional characterisation of ClC-1 variants improves clinical interpretation of their pathogenicity and inheritance pattern and serve as reference for 34 previously unreported and 28 previously uncharacterised CLCN1 variants. In addition, we identify novel pathogenic mechanisms and find that variants that alter voltage dependence of activation cluster in the first half of the transmembrane domains and variants that yield no currents cluster in the second half of the transmembrane domain. None of the variants in the intracellular domains were associated with dominant functional features or dominant inheritance pattern of MC. Our data help provide an initial estimate of the anticipated inheritance pattern based on the location of a novel variant and shows that systematic functional characterisation can significantly refine the assessment of risk of an associated inheritance pattern and consequently the clinical and genetic counselling.

Our work aims to reflect on the reasons that guide the enshrining of the rules related to advertising directed to minors, with particular emphasis on the most recent restrictions on advertising directed to minors under 16 years related to foodstuffs and beverages that contain high energy value, content of salt, sugar, saturated fatty acids and processed fatty acids. Despite the progress related to the protection of children and young people, other problems persist and/or are aggravated, demanding a serious debate, resulting in urgent responses. Among such problems, obesity, often as a result of childhood, is a chronic and complex disease, with an increasing prevalence worldwide and considered by the World Health Organization as the global epidemic of the 21st century, while, on the other side of the balance, malnutrition appears as the main cause of death of children in some countries, especially on the African continent. The reasons that guided our interest and choice in the approach of the present theme are precisely due to the realization of such realities that are so different from one another: on the one hand, the epidemic of childhood obesity, often leading to bullying, namely developed in a school context, a phenomenon that comprises multiple realities and variants of intimidation, aggression and harassment, of a physical or psychological nature and that, essentially, is characterized by the repetition of acts performed by one or more aggressors against another member of the same school community who, for various reasons, such as childhood obesity, it is in a situation of greater fragility; on the other hand, the disturbing malnutrition of thousands of children. The discussion around such realities, with food as a common denominator, cannot ordinarily neglect the concept of sustainable consumption, which is also of capital importance and which marks the current political, economic and social discourses. If there were any doubts as to its importance, the Universal Declaration of Human Rights expressly enshrined the human right to food in the context of the right to an adequate standard of living. Its effectiveness is conditio sine qua non of health’s promotion and protection, as well as human dignity, the fight against poverty and social exclusion and, in correspondence, the construction of more just and democratic societies. We believe that, also in this area, the action of the States is essential. Democratization and fair access are necessary to guarantee the well-being of citizens. In this context, the enshrining of rules related to advertising directed to minors, although relevant, seems to be insufficient in the realization of the human right to food.

É nosso objetivo desenvolver uma reflexão sobre a regulação do exercício das responsabilidades parentais nas situações de rutura da vida em comum dos progenitores, analisando, em especial, as condições em que o tribunal pode decretar a residência alternada do filho, à luz das mais recentes alterações ao artigo 1906.º do Código Civil, operadas pela Lei n.º 65/2020 de 4 de Novembro. Cuidaremos, entre outros aspetos, da noção de residência alternada, revisitando algumas das vantagens e das desvantagens que lhe são usualmente apontadas, debruçando-nos, num segundo momento, sobre as transformações ao artigo 1906.º do Código Civil e sobre os efeitos práticos do reconhecimento expresso da residência alternada pelo legislador português, sem descurar os critérios exclusivos ou particulares que o seu decretamento deverá observar, para além da averiguação de outros aspetos relevantes e da indagação dos eventuais impactos da pandemia neste regime de responsabilidades parentais. info:eu-repo/semantics/publishedVersion

Andersen-Tawil syndrome (ATS) is a rare autosomal dominant neuromuscular disorder due to mutations in the KCNJ2 gene. The classical phenotype of ATS consists of a triad of periodic paralysis, cardiac conduction abnormalities and dysmorphic features. Episodes of either muscle weakness or cardiac arrhythmia may predominate however, and dysmorphic features may be subtle, masking the true breadth of the clinical presentation, and posing a diagnostic challenge. The severity of cardiac involvement varies but includes reports of life-threatening events or sudden cardiac death, usually attributed to ventricular tachyarrhythmias. We report the first case of advanced atrioventricular (AV) block in ATS and highlight clinical factors that may delay diagnosis.

This paper targets a timely reflection and analysis on the subject of shareholder agreements on the exercise of management functions, as the same is treated, in particular in relation to the prohibition under Article 17, paragraph 2, in fine. The fundamental importance of this matter is showed when we consider the role played by shareholder agreements in business practice, in particular in the life of the companies and the natural tendency of partners to influence the conduct of members of the Board of Directors and the fate of companies. Sometimes such agreements even appear as substitutes instruments of the normal decision-making process, taking into account its complementary role in relation to the statutory elements. The emphasis that is now being placed on the institutional aspect of society, alongside the promotion of contractual relations through the conclusion of such agreements also indicate the timeliness of discussion on the issue of shareholders' agreements in general and therefore the modernity of that which is our subject of investigation. KEYWORDS: shareholder agreements; management; principle of tipicity; competence distribution rules; social interest., O presente trabalho almeja uma reflexão e análise oportunas em torno da temática dos acordos parassociais sobre o exercício de funções de administração, tal como a mesma é tratada, em especial, na sua relação com a proibição prevista no artigo 17.º, n.º 2, in fine, do Código das Sociedades Comerciais. Este assunto apresenta importância fundamental se considerarmos o papel assumido pelos acordos parassociais na prática dos negócios e, em particular, na vida das sociedades, assim como a tendência natural dos sócios para influenciar a conduta dos membros dos órgãos de administração e o destino da sociedade. Tais acordos aparecem mesmo, frequentemente, como instrumentos sucedâneos dos normais mecanismos decisórios, tendo em conta a sua função complementadora em relação aos elementos estatutários. O acento tónico que começa agora a ser colocado no aspecto institucional da sociedade, a par da promoção das relações contratuais por via da celebração deste tipo de acordos, indiciam também a actualidade da discussão em torno da temática dos acordos parassociais em geral e, por conseguinte, a modernidade daquele que é o nosso objecto de investigação.

Tese de Doutoramento em Direito, no ramo de Ciências Jurídico-Empresariais, apresentada à Faculdade de Direito da Universidade de Coimbra Pese embora acreditarmos ter-se constatado um desenvolvimento expressivo em matéria de acordos parassociais, quer no plano da vida prática, quer no plano da reflexão teórica, não se olvida que a investigação em torno da temática em apreciação constitui ainda uma matéria de inquestionável interesse e relevância, tendo em conta a importância que os acordos parassociais assumem na vida das sociedades, assim como pela complexidade que a problemática encerra, reclamando uma profunda e apurada compreensão dos mecanismos de construção jurídica da sociedade comercial, onde estes acordos ocupam um lugar cimeiro, numa época pautada pela constante mutação vivenciada no universo do direito societário, não apenas a nível nacional como internacional. Instrumento de estabilidade e unidade da vida da empresa, os acordos parassociais desempenham uma função de integração e regulamentação das normas compreendidas no contrato de sociedade, criando vínculos que são assumidos pelos sócios, entre eles ou perante a sociedade e terceiros. Não obstante a sua relevância e frequência, a investigação em torno da figura depara-se com obstáculos relativos ao escrutínio da verdadeira extensão do fenómeno, resultado de práticas de carácter reservado e da escassez de decisões jurisprudenciais na matéria. Quanto a nós, a matéria dos acordos parassociais encontra-se ainda insuficientemente estudada em determinados aspectos essenciais, vislumbrando-se pela leitura de alguma bibliografia e jurisprudência, a persistência de algumas questões ainda por debater e deslindar, razão pela qual nos propomos trazer para a discussão uma perspectiva algo diferente. O período de relutância manifestada pela jurisprudência e pela doutrina em relação à celebração de acordos parassociais encontra-se agora ultrapassado diante a constatação de uma sua utilização cada vez mais frequente e o reconhecimento das vantagens a ela associadas. Em todo o caso, a consagração, entre nós, da regra geral de admissibilidade dos acordos parassociais, assim como a superação da querela doutrinal e jurisprudencial em torno desta figura, aqui e além-fronteiras, mais não são senão o ponto de partida, não encerrando o seu expresso reconhecimento a discussão em torno de determinadas questões, como seja a da definição dos limites ao conteúdo daqueles convénios, assim como as diversas dificuldades que a temática suscita, de entre as quais a da contraposição entre a socialidade e a parassocialidade. Tradicionalmente, a generalidade da doutrina distingue entre contrato de sociedade e contrato parassocial no plano da diversidade de regimes, apontando, para tanto, cinco critérios, que traduzem diferenças ao nível da constituição, da validade, da eficácia, da interpretação e da modificação dos esquemas negociais. Porém, um tal modo de análise não se adequa às mais recentes concepções dogmáticas acerca da parassocialidade, em especial no que ao confronto com o contrato de sociedade respeita, designadamente por não ilustrar as relações que se estabelecem entre os dois planos. Por todo o exposto, o confronto entre as situações jurídicas sociais e as situações jurídicas parassociais há-de comportar dois graus de análise sucessiva: a problemática deve, primeiro, ser examinada de um ponto de vista dogmático, e apenas depois, determinados os efeitos ao nível do regime. Se é verdade que a análise dos vínculos parassociais como expressões de vontade individual dos sócios deve ter-se hoje por ultrapassada em benefício do seu enquadramento como modo de regulação societária com potencialidades organizativas, também o contributo das teses formalistas na delimitação da matéria parassocial não pode aceitar-se integralmente. Numa apreciação geral da problemática, o posicionamento recíproco das regras societárias e dos acordos parassociais afigura-se móvel, no sentido de que aquele não obedece sempre e de modo unívoco à ideia comummente difundida de que os acordos parassociais são acessórios e intervêm secundariamente, ao lado, ou para além, das regras jussocietárias. Na realidade, a existência de numerosos limites de validade dos acordos parassociais que decorrem do funcionamento do sistema societário coloca em crise a teoria da separação entre relações estatutárias e relações parassociais, obrigando a reenquadrar os dois níveis de composição de interesses societários de modo unitário. Partindo dessa constatação, a construção jurídica da parassocialidade, no confronto com a socialidade, deve fazer-se agora, não em termos estritamente bipolares, segundo duas alternativas e sem zonas intermédias, mas antes em termos gradativos, em função de determinados critérios (a representatividade, a duração e o grau de vinculação), tudo a apontar no sentido da actual crise da “teoria da separação” entre relação societária e relação parassocial e superação do denominado dogma da acessoriedade. Despite significant developments in the area of shareholders’ agreements, both in terms of practical life and in theoretical reflection, research in this field still constitutes a matter of unquestionable interest and relevance. This is duly supported by their importance in companies lives, as well as the complexity of the topic in an era ruled by constant mutation of national and international corporate law, which demand a deep and accurate understanding of the mechanisms behind the legal construction of the companies. Being an instrument of stability and unity of the company’s life, shareholders’ agreements play a role of integration and regulation of the rules included in the articles of association, creating bonds that are assumed by the shareholders, among them or before society and third parties. Despite their relevance and frequency, the research around shareholders’ agreements is hampered in the scrutiny of the true extent of the phenomenon, as the result of practices of a reserved nature and the lack of jurisprudential decisions in this matter. From our point of view, shareholders’ agreements are insufficiently studied regarding certain essential aspects. Taking into account relevant literature and jurisprudence concerning this subject we recognize the persistence of some issues that still need to be debated and delineated. And that is the reason why we now intend to bring into the discussion a somewhat different perspective. The period of reluctance expressed by jurisprudence and doctrine in relation to the conclusion of shareholders’ agreements is now outweighed, especially because they are being used more and more often, and also as the result of the recognition of their advantages. The consecration of the general rule of the admissibility of shareholders’ agreements, as well as the overcoming of the doctrinal and jurisprudential quarrel around this figure, in Portugal and abroad, are nothing more than the starting point. Their recognition does not settle the discussion concerning other issues, such as the definition of the limits to the content of those agreements and the various difficulties that the theme raises namely on the contraposition between sociality and the parasociality. Traditionally, most doctrine distinguishes between articles of association and shareholders’s agreements in terms of diversity of regimes, pointing to five criteria that translate differences in the constitution, validity, effectiveness, interpretation and modification of the negotiation schemes. However, such analysis is inadequate according to the most recent dogmatic conceptions concerning shareholders’ agreements especially regarding their relation to the articles of association, and namely because it does not illustrate the relations that are established between them. From the aforementioned arguments, the confrontation between social and parasocial juridical situations must have two degrees of successive analysis: the problematic must be first examined from a dogmatic point of view, and only then should the effects be determined regarding the applicable regime. Although the analysis of shareholders’ agreements as the expression of the individual will of shareholders must be now considered overwhelmed in favour of their setting as a type of corporate regulation with organizational potentialities, the contribution of the formalist theses in the delimitation of shareholders’ agreements cannot be fully accepted. In a general appreciation of the problem, the reciprocal positioning of corporate rules and shareholders’ agreements seems to be mobile, in the sense that it does not always obey the commonly held view that shareholders’ agreements are secondary and intervene secondarily, alongside, or beyond, corporate law. In reality, the existence of several limits of validity of shareholders’ agreements that result from the functioning of the corporate system questions the theory of the separation between the statutory relations and those that emerge from shareholders’ agreements, which forces the reframing of the two composition levels of corporate interests in a unitary way. Based on this finding, the legal construction of parasociality, when in the confrontation with sociality, must now be done in gradual terms, rather than strictly in bipolar terms, according to two alternatives and without intermediate zones. Furthermore, this should be done according to certain criteria (representativeness, duration and degree of linkage), all pointing out to the current crisis of the “theory of separation” between corporate relationship and shareholders’ agreements relationship and to the overcoming of the so-called “dogma of accessory”.

O presente trabalho almeja uma reflexão em torno da questão de saber em que medida devemos recear como discriminatório, por contrário à igualdade de género e remissivo para a secundarização e sombra social e histórica das Mulheres, aquilo a que insistentemente se tem denominado de (síndrome de) alienação parental, quantas vezes invocada, sob a égide do superior interesse da criança, na ausência de acordo dos pais, nos processos de regulação das responsabilidades parentais, especialmente nos emergentes de situações de ruptura da vida em comum dos progenitores, a indiciar a indispensabilidade da discussão e atenção redobrada numa área em contínua evolução, marcando a actualidade do discurso no ramo do Direito da Família. Tema particularmente sensível, permeável a ideias pré-concebidas ou estereótipos e lugares comuns, ele impõe uma investigação cuidada, sem esquecer que o superior interesse da criança deverá ser, em primeira linha, o critério orientador da decisão.

This paper aims to reflect on the theme of International Child Abduction, as it is especially treated in the Council Regulation (EC) No 2201/2003. This issue appears to be truly present nowadays, taking into account not only the vulnerability of the individuals concerned, as well the fact that this is a time characterized by progressive and relevant changes, which understandably not fail to act in our area of study. Now, more than ever, the Family Law, as it is said, does not know borders. Notwithstanding the importance of this trend, we cannot forget that some problems get worse in situations when the disputes assume a cross-border dimension. The distrust of foreign authorities, alongside nationalism, often exacerbated, certainly make the effectiveness of the decisions on the regulation of parental responsibilities difficult. Therefore, the same constraints must yield and give way to the establishment of mechanisms of cooperation and trust between States oriented to the achievement of a major objective, namely the defense of the best interests of the child., O presente trabalho almeja uma reflexão em torno da temática do rapto internacional de crianças, tal como a mesma é abordada em especial na sua relação com os respectivos instrumentos de resolução.Este assunto apresenta, de resto, inquestionável actualidade, tendo em conta não apenas a vulnerabilidade dos sujeitos em causa, como a circunstância de esta ser uma época marcada por progressivas mutações de relevo, que compreensivelmente não deixam de actuar também no domínio que ora nos ocupa.Hoje, mais do que nunca, o Direito da Família, sobretudo nos países ocidentais, diz-se, não conhecer fronteiras, aludindo-se, a propósito, à sua crescente internacionalização. Sem prescindir da importância capital desta tendência, não se olvida que alguns problemas se agravam nas situações em que o litígio assuma uma dimensão transfronteiriça.A desconfiança perante as autoridades estrangeiras, a par do nacionalismo, quantas vezes exacerbado, certamente dificultam a efectividade das decisões em matéria de regulação de responsabilidades parentais, pelo que os mesmos condicionalismos devem ceder para dar lugar ao estabelecimento de mecanismos de cooperação e confiança entre os Estados, dirigidos à concretização de um objectivo primordial, qual seja o da defesa do superior interesse da criança.

OBJECTIVE: To characterize the phenotype of patients with symptoms of periodic paralysis (PP) and ryanodine receptor (RYR1) gene mutations.METHODS: Cases with a possible diagnosis of PP but additional clinicopathologic findings previously associated with RYR1-related disorders were referred for a tertiary neuromuscular clinical assessment in which they underwent detailed clinical evaluation, including neurophysiologic assessment, muscle biopsy, and muscle MRI. Genetic analysis with next-generation sequencing and/or targeted Sanger sequencing was performed.RESULTS: Three cases with episodic muscle paralysis or weakness and additional findings compatible with a RYR1-related myopathy were identified. The McManis test, used in the diagnosis of PP, was positive in 2 of 3 cases. Genetic analysis of known PP genes was negative. RYR1 analysis confirmed likely pathogenic variants in all 3 cases.CONCLUSIONS: RYR1 mutations can cause late-onset atypical PP both with and without associated myopathy. Myalgia and cramps are prominent features. The McManis test may be a useful diagnostic tool to indicate RYR1-associated PP. We propose that clinicopathologic features suggestive of RYR1-related disorders should be sought in genetically undefined PP cases and that RYR1 gene testing be considered in those in whom mutations in SCN4A, CACNA1S, and KCNJ2 have already been excluded.

Trabalho apresentado no 2.º Simpósio Nacional de Fruticultura que decorreu em Castelo Branco, na Escola Superior Agrária do Instituto Politécnico de Castelo Branco, de 4 a 5 de Fevereiro de 2010. A espectroscopia NIR é uma técnica não destrutiva de previsão da qualidade de frutos bastante promissora para o sector frutícola, mas que necessita de aferição através das metodologias convencionais destrutivas. No presente trabalho foram analisados 1920 frutos das cultivares de ameixeira japonesa “Black-Amber”, “Black Ruby”, “Fortune”, “Golden Globe”, “Songold” e “Angeleno”, para determinação da dureza da polpa e do teor em sólidos solúveis totais (TSS) através do NIR CASE e calibração/validação pelos respectivos métodos destrutivos de referência. Relativamente à dureza da polpa a baixa correlação obtida demonstra que a metodologia NIRS é desadequada para a previsão deste parâmetro: o coeficiente de determinação variou entre r2=0,05 na “Black Amber”, r2=0,12 na “Black Ruby”, r2=0,18 na “Fortune”, r2=0,82 na Golden Globe”, r2=0,05 na “Songold” e r2=0,47 na “Angeleno”. Para os TSS os valores previstos pelos modelos apresentaram correlação mais elevada com os valores determinados destrutivamente, apresentando um coeficiente de determinação superior a 0,77 para todas as cultivares com excepção da “Black Amber” que apresentou um coeficiente r2=0,29. A “Golden Globe” apresentou os melhores resultados de previsão para a dureza e TSS, com r2 de 0,82 e 0,78, respectivamente. Os resultados demonstram que a tecnologia NIRS pode prever com precisão o TSS de ameixas mas não se encontra adequado para prever a dureza da polpa.

Trabalho apresentado no 1.º Simpósio Nacional de Fruticultura que decorreu em Alcobaça de 12 a 13 de Outubro de 2006 e que foi organizado pela Associação Portuguesa de Horticultura. Neste trabalho, apresentam-se resultados preliminares relativos a alguns sub-modelos da produção de pêra ‘Rocha’: crescimento do fruto, relação entre a carga de frutos e a produção da árvore, influência do volume da copa (compasso de plantação, idade) na produtividade de árvores e pomares.